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Originally published as JCO Early Release 10.1200/JCO.2005.12.914 on April 11 2005 © 2005 American Society of Clinical Oncology.
Fertility After Breast Cancer: Questions AboundDana-Farber Cancer Institute and Brigham and Women's Hospital and Harvard Medical School, Boston, MA Women of childbearing age represent a relatively small minority of women diagnosed with breast cancer. However, young women bear an inordinate share of the burden; they are more likely to die of their disease, more likely to experience psychosocial distress, and more likely to have impairment of their long-term quality of life. For many young women, a diagnosis of breast cancer occurs at a time when fertility and family planning are a major focus. As a consequence, concerns about infertility may contribute to their emotional distress. The risk of temporary amenorrhea or permanent menopause seem to be related to patient age and treatment received.1-5 Modern hormonal treatments do not generally cause permanent infertility, but pregnancy is contraindicated during hormonal therapy, and fertility declines with age. Furthermore, some women may be advised to wait several years before trying to conceive. Thus, strategies to preserve fertility are of great interest to many young women when facing a breast cancer diagnosis and making treatment decisions.6 There are several considerations for women who are interested in having a biologic child after a diagnosis of breast cancer. The administration of adjuvant chemotherapy substantially affects the likelihood of infertility. For some women, forgoing chemotherapy is a very reasonable consideration, particularly if the tumor is small, node negative, and hormone receptor positive. For women who receive cytotoxic chemotherapy, regimens vary with regard to the risk of resulting amenorrhea. For example, in women under 40 years old, four cycles of conventional doxorubicin and cyclophosphamide chemotherapy confers a risk of amenorrhea of 10% to 15% compared with a risk of 20% to 60% after six cycles of cyclophosphamide, epirubicin, and fluorouracil or cyclophosphamide, methotrexate, and fluorouracil.3,5 The effects of the taxanes and dose-dense treatment, both increasingly used in the adjuvant setting, have not been thoroughly evaluated. Several pilot studies have evaluated the use of ovarian suppression with luteinizing hormone–releasing hormone analogs during chemotherapy, but these studies have not been definitive. An ongoing randomized phase III study sponsored by the Southwest Oncology Group will determine the impact of ovarian suppression during chemotherapy on preservation of fertility. Of course, continued menstruation does not necessarily equate with fertility, especially as women age. There is evidence in pediatric cancer survivors that ovarian reserve after cytotoxic chemotherapy may be depleted despite continued menstrual cycling,7 although few data are available regarding this issue in adult survivor populations. Techniques to cryopreserve eggs, ovarian tissue, and embryos before treatment are currently available. Despite recent progress,8,9 cryopreservation of ovarian tissue or oocytes remains experimental. Embryo cryopreservation after oocyte retrieval and in vitro fertilization (IVF) is an effective and widely available procedure that can be performed before initiation of systemic treatment. However, concerns about the safety of markedly elevated estrogen levels associated with conventional ovarian stimulation using follicle-stimulating hormone (FSH) have limited enthusiasm for this strategy. In this issue, Oktay et al10 build on previous experience using alternative ovarian stimulation strategies in young women with breast cancer. Their goal was to minimize the surge in estradiol levels seen with traditional ovarian stimulation and to maximize the number of eggs that could be harvested.10 In a previous study, Oktay et al11 reported that tamoxifen stimulation resulted in a greater number of embryos per patient compared with a historical control group who had undergone natural-cycle IVF (IVF without pharmacologic stimulation). Although the tamoxifen stimulation strategy was associated with transiently higher estradiol levels, the presence of tamoxifen may abrogate any detrimental impact of elevated estrogens. In the present study, Oktay et al10 studied hormonal levels, IVF embryo yield, pregnancy rates, and rates of disease recurrence in a prospective cohort of women who underwent one of the following three ovarian stimulation approaches: tamoxifen alone (n = 12), tamoxifen with FSH (n = 11), and letrozole with FSH (n = 11). A control group (n = 31), comprised of women who had been offered participation in the study but who had chosen not to undergo ovarian stimulation, was also observed for disease outcomes. The authors found that ovarian stimulation with letrozole-FSH or tamoxifen-FSH resulted in a greater embryo yield than tamoxifen alone.10 Although the difference in number of embryos between the letrozole-FSH and tamoxifen-FSH groups did not reach statistical significance, the authors suggest that letrozole-FSH stimulation leads to an embryo yield that is comparable to conventional FSH stimulation in noncancer patients. Letrozole-FSH and tamoxifen-alone stimulation were associated with significantly lower peak estradiol levels than tamoxifen-FSH stimulation. These data prompt several questions. Does a relatively brief exposure to high estrogen levels affect risk of recurrence in young women with newly diagnosed early breast cancer? Does the use of tamoxifen mitigate the potential risk of transiently high estrogen levels? Premenopausal women on chronic tamoxifen therapy are known to have elevated estradiol levels,12-14 and yet, tamoxifen improves survival in women with hormone receptor–positive early breast cancer.15 Does letrozole-FSH stimulation, resulting in lower though still elevated estrogen levels, attenuate potential risk? Could a brief exposure to tamoxifen or letrozole before treatment compromise the benefits of chemotherapy? In postmenopausal women, the administration of tamoxifen with chemotherapy seems to be less effective than sequential treatment.16 And finally, does tamoxifen or letrozole have an influence on the quality of oocytes harvested in light of evidence that the drug regimen used for ovarian stimulation can affect pregnancy rates in other IVF populations?17 There are no clear answers to these questions. Most notably, the small sample size, short follow-up, and nonrandom nature of the study presented by Oktay et al10 preclude any definitive conclusions about the safety of IVF using any of these strategies from the standpoint of breast cancer recurrence. Because there has been increasing attention paid to survivorship issues in oncology, it is important to consider reproductive health after diagnosis and treatment. The report by Oktay et al10 presents a promising new approach to ovarian stimulation for women desiring to undergo IVF in the setting of early-stage breast cancer. Ultimately, the number of women for whom these strategies result in a pregnancy that otherwise would not have been possible remains unknown. Given the low pregnancy rates reported in the study by Oktay et al,10 the true benefit of these strategies has yet to be determined. It is unlikely that there will ever be a randomized trial to evaluate the safety and efficacy of IVF before breast cancer treatment. At present, women with newly diagnosed breast cancer who are interested in fertility preservation should carefully weigh the potential risks and benefits of IVF before treatment, recognizing the limitations of the available data. A more extensive experience that details both pregnancy and disease outcomes after IVF would be helpful to women and their physicians who are making these difficult decisions. Those women who pursue IVF should be encouraged to participate in registries and clinical studies, such as those conducted by Oktay et al, to more fully characterize risks and benefits. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Valagussa P, De Candis D, Antonelli G, et al: VIII. Women's health perception and breast cancer: Issues of fertility, hormone substitution, and cancer prevention. Recent Results Cancer Res 140:277-283, 1996[Medline] 2. Hortobagyi GN, Buzdar AU, Marcus CE, et al: Immediate and long-term toxicity of adjuvant chemotherapy regimens containing doxorubicin in trials at M.D. Anderson Hospital and Tumor Institute. NCI Monogr 1:105-109, 1986
3. Goodwin PJ, Ennis M, Pritchard KI, et al: Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17:2365-2370, 1999 4. Minton SE, Munster PN: Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control 9:466-472, 2002[Medline] 5. Burstein HJ, Winer EP: Reproductive issues, in Harris JR (ed): Diseases of the Breast (ed 2). Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 1051-1059
6. Partridge AH, Gelber S, Peppercorn J, et al: Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 22:4174-4183, 2004
7. Bath LE, Wallace WH, Shaw MP, et al: Depletion of ovarian reserve in young women after treatment for cancer in childhood: Detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 18:2368-2374, 2003 8. Oktay K, Buyuk E, Veeck L, et al: Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 363:837-840, 2004[CrossRef][Medline] 9. Donnez J, Dolmans MM, Demylle D, et al: Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 364:1405-1410, 2004[CrossRef][Medline]
10. Oktay K, Buyuk E, Libertella N, et al: Fertility preservation in breast cancer patients: A prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 23:4347-4353, 2005
11. Oktay K, Buyuk E, Davis O, et al: Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 18:90-95, 2003 12. Sherman BM, Chapler FK, Crickard K, et al: Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64:398-404, 1979
13. Jordan VC, Fritz NF, Tormey DC: Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res 47:624-630, 1987
14. Jordan VC, Fritz NF, Langan-Fahey S, et al: Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst 83:1488-1491, 1991 15. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[CrossRef][Medline] 16. Albain K, Barlow W, O'Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). Breast Cancer Res Treat 88, 2004 (suppl 1, abstr 37) 17. Daya S, Gunby J, Hughes EG, et al: Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: A meta-analysis. Fertil Steril 64:347-354, 1995[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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